Studying the Mechanism of Neuronal Dysfunction in SCA7

研究 SCA7 神经元功能障碍的机制

• 批准号: 7116379
• 负责人: JENNIFER R GATCHEL
• 金额: $ 2.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-27 至 2007-03-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116379
• 关键词: amidohydrolases; ataxia; brain morphology; electrophysiology; enzyme inhibitors; gene expression; gene expression profiling; gene mutation; genetic disorder; genetic transcription; genetically modified animals; hippocampus; homopeptide; laboratory mouse; molecular pathology; nerve /myelin protein; nervous system disorder chemotherapy; neural degeneration; neural plasticity; neuropathology; neuropharmacology; nonhuman therapy evaluation; pathologic process; phenotype; synapses

DESCRIPTION (provided by applicant): Spinocerebellar ataxia 7 (SCA7) is a one of a growing group of neurodegenerative and mental disorders caused by a CAG expansion; this expansion occurs in the SCA7 gene, which encodes ataxin-7. In addition to cerebellar signs and decreased visual acuity, SCA7 patients can suffer from cognitive dysfunction and behavioral problems. Previous work in our laboratory resulted in generation of Sca7266Q/SQ knock-in (KI) and Sca7 knock-out (KO) mouse models. Sca7266Q/SQmice replicate all of the features of infantile SCA7 and have decreased post-tetantic potentiation (PTP) in hippocampal area CA1. Sca7 KO mice are unaffected and behaviorally normal, but exhibit increased PTP. Given evidence for transcriptional misregulation in Sca7266Q/5Q mice, the overall hypothesis is that ataxin-7 causes alterations in gene expression that result in the hippocampal and cerebellar phenotypes. To test this hypothesis, the extent and time course of synaptic dysfunction in mutant mice will be determined and the expression levels of candidates will be measured. In a complementary unbiased approach, expression profiling will be carried out and correlated with phenotype onset and progression. Finally, a practical approach will be taken by conducting trials of histone deacetylase;266Q/5Q (HDAC) inhibitors in Sca7 mice. These studies will provide novel insight into mechanisms of pathogenesis that occur at the level of the synapse in SCA7, and will be crucial in evaluating the efficacy of a class of therapeutic compounds in treatment of this and other polyglutamine diseases.

描述（由申请人提供）： 脊髓小脑性共济失调7（SCA 7）是由CAG扩增引起的神经退行性疾病和精神疾病之一;这种扩增发生在编码共济失调蛋白7的SCA 7基因中。除了小脑体征和视力下降外，SCA 7患者还可能患有认知功能障碍和行为问题。我们实验室之前的工作产生了Sca 7266 Q/SQ基因敲入（KI）和Sca 7基因敲除（KO）小鼠模型。 Sca 7266 Q/SQ小鼠复制了婴儿SCA 7的所有特征，并且在海马区CA 1中具有降低的强直后增强（PTP）。Sca 7 KO小鼠不受影响，行为正常，但表现出PTP增加。鉴于Sca 7266 Q/5 Q小鼠中转录失调的证据，总体假设是共济失调蛋白-7引起基因表达的改变，导致海马和小脑表型。为了检验这一假设，将确定突变小鼠中突触功能障碍的程度和时程，并测量候选物的表达水平。在互补的无偏方法中，将进行表达谱分析并与表型发作和进展相关。最后，将通过在Sca 7小鼠中进行组蛋白去乙酰化酶; 266 Q/5 Q（HDAC）抑制剂的试验来采取实用的方法。这些研究将提供新的见解发生在SCA 7的突触水平的发病机制，并将是至关重要的一类治疗化合物在治疗这种和其他多聚谷氨酰胺疾病的疗效评价。